Exo- and diastereo- selective synthesis of himbacine analogs

ABSTRACT

This application discloses a novel process for the preparation of himbacine analogs useful as thrombin receptor antagonists. The process is based in part on the use of a base-promoted dynamic epimerization of a chiral nitro center. The chemistry taught herein can be exemplified by the following:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application U.S. Ser.No. 12/505,079, which was filed Jul. 17, 2009 and is now U.S. Pat. No.7,989,653, which in turn is a divisional application of application U.S.Ser. No. 11/331,324, which was filed on Jan. 12, 2006 and matured intoU.S. Pat. No. 7,605,275 B1, which in turn claimed benefit of provisionalapplication U.S. Ser. No. 60/644,464, filed on Jan. 14, 2005, all hereinincorporated by reference.

FIELD OF THE INVENTION

This application discloses a novel process for the preparation ofhimbacine analogs useful as thrombin receptor antagonists. The processis based in part on the use of a base-promoted dynamic epimerization ofa chiral nitro center. The invention disclosed herein is related tothose disclosed in co-pending patent applications corresponding to thefollowing provisional patent applications: Ser. No. 60/643,932; Ser. No.60/643,927; and, Ser. No. 60/644,428, all four applications having beenfiled on the same date.

BACKGROUND OF THE INVENTION

Thrombin is known to have a variety of activities in different celltypes and thrombin receptors are known to be present in such cell typesas human platelets, vascular smooth muscle cells, endothelial cells, andfibroblasts. Thrombin receptor antagonists may be useful in thetreatment of thrombotic, inflammatory, atherosclerotic andfibroproliferative disorders, as well as other disorders in whichthrombin and its receptor play a pathological role. See, for example,U.S. Pat. No. 6,063,847, the disclosure of which is incorporated byreference.

One thrombin receptor antagonist is a compound of the formula:

This compound is an orally bioavailable thrombin receptor antagonistderived from himbacine. Compound 11 may be synthesized from Compound 1:

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl,alkylaryl, arylalkyl, and heteroaryl groups.

Processes for the synthesis of similar himbacine analog thrombinreceptor antagonists are disclosed in U.S. Pat. No. 6,063,847, and U.S.publication no. 2003/0216437, methods of using thrombin receptorantagonists are disclosed in U.S. publication no. 2004/0192753, and thesynthesis of the bisulfate salt of a particular himbacine analog isdisclosed in U.S. publication no. 2004/0176418, now U.S. Pat. No.7,235,567, the disclosures of which are incorporated by referenceherein. The present application provides a novel process for preparingCompound 11 from Compound 1, which process provides an improved yieldand the elimination of the need for a chiral intermediate.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a process for preparingCompound 1:

said process comprising the steps of:

(a) cyclizing Compound 2 in a first solvent at an elevated temperature

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl,alkylaryl, arylalkyl, heterocyclic and heteroaryl groups, or R₅ and R₆,together with the nitrogen to which they are attached, form a 3- to6-membered heterocyclic compound containing 1-4 heteroatoms, to producea first mixture of exo isomers

said isomers having a trans-[5,6]-ring-junction and endo isomers:

(b) epimerizing said trans-[5,6]-ring-junction in Compound 29 bytreating said first mixture with a first base to produce a secondmixture comprising cis-[5,6]ring-junction-nitro-α isomer andcis-[5,6]-ring-junction-nitro-β isomer of Compound 30:

and

(c) treating said second mixture with a second solvent, causing saidα-isomer of Compound 30 to precipitate to produce Compound 1.

In another embodiment, the above process further comprises the step oftreating said second mixture with a second base, resulting in a dynamicresolution of said second mixture, in which said β-isomer of Compound 30is converted to α-isomer of Compound 30, and α-isomer of Compound 30 isprecipitated to produce Compound 1.

In another embodiment, said first solvent is selected from the groupconsisting of xylene, N-methylpyrrolidinone, Dimethylsulfoxide, diphenylether, Dimethylacetamide, and mixtures of 2 or more thereof.

In another embodiment, said temperature is between about 70 and about190° C., preferably between about 80 and about 170° C., more preferablybetween about 100 and about 160° C., still more preferably between about120 and about 150° C.

In another embodiment, said first base is selected from the groupconsisting of triethylamine, 1,5-diazabicyclo[4,3,0]non-5-ene1,4-diazabicyclo[2,2,2]octane, and 1,8-diazabicyclo[5,4,0]undec-7-ene,and mixtures of 2 or more thereof.

In another embodiment, said second solvent is selected from the groupconsisting of alcohols, ethers, ketones, esters, xylene,N-methylpyrrolidinone, and mixtures of 2 or more thereof.

In another embodiment, the invention provides a process for preparingCompound 2:

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl,alkylaryl, arylalkyl, heterocyclic and heteroaryl groups, or R₅ and R₆,together with the nitrogen to which they are attached, form a 3- to6-membered heterocyclic compound containing 1-4 heteroatoms, saidprocess comprising:

(a) converting (R)-butynol to Compound 3:

(b) reducing Compound 3 to yield Compound 4:

and,

(c) reacting Compound 4 with Compound 6:

to yield Compound 2.

In yet another embodiment, the invention is directed to a process forpreparing Compound 2:

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl,alkylaryl, arylalkyl, heterocyclic and heteroaryl groups, or R₅ and R₆,together with the nitrogen to which they are attached, form a 3- to6-membered heterocyclic compound containing 1-4 heteroatoms, saidprocess comprising:

(a) converting (R)-butynol to Compound 3:

(b) reacting Compound 3 with Compound 6 to yield Compound 7:

(c) reducing Compound 7 to produce Compound 2:

In another embodiment, the invention provides the following compounds:

A further understanding of the invention will be had from the followingdetailed description of the invention.

DESCRIPTION OF THE INVENTION

The following definitions and terms are used herein or are otherwiseknown to a skilled artisan. Except where stated otherwise, thedefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“alkoxy,” etc.

Unless otherwise known, stated or shown to be to the contrary, the pointof attachment for a multiple term substituent (two or more terms thatare combined to identify a single moiety) to a subject structure isthrough the last named term of the multiple term substituent. Forexample, a cycloalkylalkyl substituent attaches to a targeted structurethrough the latter “alkyl” portion of the substituent (e.g.,structure-alkyl-cycloalkyl).

The identity of each variable appearing more than once in a formula maybe independently selected from the definition for that variable, unlessotherwise indicated.

Unless stated, shown or otherwise known to be the contrary, all atomsillustrated in chemical formulas for covalent compounds possess normalvalencies. Thus, hydrogen atoms, double bonds, triple bonds and ringstructures need not be expressly depicted in a general chemical formula.

Double bonds, where appropriate, may be represented by the presence ofparentheses around an atom in a chemical formula. For example, acarbonyl functionality, —CO—, may also be represented in a chemicalformula by —C(O)—, or —C(═O)—. One skilled in the art will be able todetermine the presence or absence of double (and triple bonds) in acovalently-bonded molecule. For instance, it is readily recognized thata carboxyl functionality may be represented by —COON, —C(O)OH, —C(═O)OHor —CO₂H.

The term “heteroatom,” as used herein, means a nitrogen, sulfur oroxygen atom. Multiple heteroatoms in the same group may be the same ordifferent.

As used herein, the term “alkyl” means an aliphatic hydrocarbon groupthat can be straight or branched and comprises 1 to about 24 carbonatoms in the chain. Preferred alkyl groups comprise 1 to about 15 carbonatoms in the chain. More preferred alkyl groups comprise 1 to about 6carbon atoms in the chain. “Lower alkyl” means alkyl groups of 1 to 6carbon atoms in the chain. “Branched” means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkylchain. The alkyl can be substituted by one or more substituentsindependently selected from the group consisting of halo, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂ (which alkyls can be the same or different),carboxy and —C(O)O-alkyl. Non-limiting examples of suitable alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl,heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl andcyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group (straight or branchedcarbon chain) comprising one or more double bonds in the chain and whichcan be conjugated or unconjugated. Useful alkenyl groups can comprise 2to about 15 carbon atoms in the chain, preferably 2 to about 12 carbonatoms in the chain, and more preferably 2 to about 6 carbon atoms in thechain. The alkenyl group can be substituted by one or more substituentsindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano and alkoxy. Non-limiting examples of suitable alkenylgroups include ethenyl, propenyl, n-butenyl, 3-methylbut-enyl andn-pentenyl.

Where an alkyl or alkenyl chain joins two other variables and istherefore bivalent, the terms alkylene and alkenylene, respectively, areused.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Useful alkoxy groups can comprise 1 to about 12carbon atoms, preferably 1 to about 6 carbon atoms. Non-limitingexamples of suitable alkoxy groups include methoxy, ethoxy andisopropoxy. The alkyl group of the alkoxy is linked to an adjacentmoiety through the ether oxygen.

The term “cycloalkyl” as used herein, means an unsubstituted orsubstituted, saturated, stable, non-aromatic, chemically-feasiblecarbocyclic ring having preferably from three to fifteen carbon atoms,more preferably, from three to eight carbon atoms. The cycloalkyl carbonring radical is saturated and may be fused, for example, benzofused,with one to two cycloalkyl, aromatic, heterocyclic or heteroaromaticrings. The cycloalkyl may be attached at any endocyclic carbon atom thatresults in a stable structure. Preferred carbocyclic rings have fromfive to six carbons. Examples of cycloalkyl radicals includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or thelike.

“Alkynyl” means an aliphatic hydrocarbon group comprising at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 10 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. Non-limiting examples ofsuitable alkynyl groups include ethynyl, propynyl, 2-butynyl,3-methylbutynyl, n-pentynyl, and decynyl. The alkynyl group may besubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of alkyl, aryl and cycloalkyl.

The term “aryl,” as used herein, means a substituted or unsubstituted,aromatic, mono- or bicyclic, chemically-feasible carbocyclic ring systemhaving from one to two aromatic rings. The aryl moiety will generallyhave from 6 to 14 carbon atoms with all available substitutable carbonatoms of the aryl moiety being intended as possible points ofattachment. Representative examples include phenyl, tolyl, xylyl,cumenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, or the like. Ifdesired, the carbocyclic moiety can be substituted with from one tofive, preferably, one to three, moieties, such as mono- throughpentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy,amino, monoalkylamino, dialkylamino, or the like.

“Heteroaryl” means a monocyclic or multicyclic aromatic ring system ofabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the atoms in the ring system is/are atomsother than carbon, for example nitrogen, oxygen or sulfur. Mono- andpolycyclic (e.g., bicyclic) heteroaryl groups can be unsubstituted orsubstituted with a plurality of substituents, preferably, one to fivesubstituents, more preferably, one, two or three substituents (e.g.,mono- through pentahalo, alkyl, trifluoromethyl, phenyl, hydroxy,alkoxy, phenoxy, amino, monoalkylamino, dialkylamino, or the like).Typically, a heteroaryl group represents a chemically-feasible cyclicgroup of five or six atoms, or a chemically-feasible bicyclic group ofnine or ten atoms, at least one of which is carbon, and having at leastone oxygen, sulfur or nitrogen atom interrupting a carbocyclic ringhaving a sufficient number of pi (π) electrons to provide aromaticcharacter. Representative heteroaryl (heteroaromatic) groups arepyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, benzofuranyl,thienyl, benzothienyl, thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl,triazolyl, isothiazolyl, benzothiazolyl, benzoxazolyl, oxazolyl,pyrrolyl, isoxazolyl, 1,3,5-triazinyl and indolyl groups.

The term “heterocyclic ring” or “heterocycle,” as used herein, means anunsubstituted or substituted, saturated, unsaturated or aromatic,chemically-feasible ring, comprised of carbon atoms and one or moreheteroatoms in the ring. Heterocyclic rings may be monocyclic orpolycyclic. Monocyclic rings preferably contain from three to eightatoms in the ring structure, more preferably, five to seven atoms.Polycyclic ring systems consisting of two rings preferably contain fromsix to sixteen atoms, most preferably, ten to twelve atoms. Polycyclicring systems consisting of three rings contain preferably from thirteento seventeen atoms, more preferably, fourteen or fifteen atoms. Eachheterocyclic ring has at least one heteroatom. Unless otherwise stated,the heteroatoms may each be independently selected from the groupconsisting of nitrogen, sulfur and oxygen atoms.

The terms “Hal,” “halo,” “halogen” and “halide,” as used herein, mean achloro, bromo, fluoro or iodo atom radical. Chlorides, bromides andfluorides are preferred halides.

The term “carbonate”, as used herein, is understood to includebicarbonates.

The term “isomer”, as used herein, is understood to mean one of two ormore molecules having the same number and kind of atoms and hence thesame molecular weight, but differing in respect to the arrangement orconfiguration of the atoms.

The term “epimerizing”, as used herein, is understood to mean convertingfrom one isomer to another, wherein it is the relative position of anattached H that differs between the two isomers.

The term “precipitate”, as used herein, is understood to mean to fallout of solution as a solid.

The term “dynamic resolution”, as used herein, is understood to mean aprocess in which a conversion from a first isomer to a second isomer ofthe same compound in a solution is thermodynamically driven by thedepletion of the second isomer from the solution by precipitation of thesecond isomer.

The following abbreviations are defined: EtOH is ethanol; Me is methyl;Et is ethyl; Bu is butyl; n-Bu is normal-butyl, t-Bu is Cert-butyl, OAcis acetate; KOt-Bu is potassium Cert-butoxide; NBS is N-bromosuccinimide; NMP is 1-methyl-2-pyrrolidinone; DMAP is4-dimethylaminopyridine; THF is tetrahydrofuran; DBU is1,8-diazabicyclo[5,4,0]undec-7-ene; DMA is N,N-dimethylacetamide;n-Bu₄NBr is tetrabutylammonium bromide; n-Bu₄NOH is tetrabutylammoniumhydroxide, n-Bu₄N(HSO₄) is tetrabutylammonium hydrogen sulfate, and“equiv.” or “eq.” means equivalents.

“n”, as it is used herein, is understood to be an integer having a valuethat is inclusive of the range recited thereafter. Thus “n is between 0and 4” and “n ranges 0-4” both mean that n may have any of the values 0,1, 2, 3 or 4.

General Syntheses

The following scheme summarizes the dynamic resolution-based approach tosynthesizing Compound 11 from (R)-butynol:

(R)-butynol may be converted to amide 3 by either of Methods A or B:

Preparation of Amide-Method A:

Preparation of Amide-Method B:

In each of methods A and B, P is a protecting group, for example THP orSiR¹R²R³, wherein R¹-R³ may be H, alkyl, alkenyl, cycloalkyl, aryl,arylalkyl, alkylaryl, heterocyclic, and heteroaryl groups, Y is selectedfrom the group consisting of Cl, Br, I, and R′″COO, wherein R′″ isselected from the group consisting of alkyl, aryl, alkylaryl, andarylalkyl and X is a leaving group. By way of example, X can be halogen,for example Cl, Br, or I. As another example, X can be selected fromheterocyclic rings, such as imidazoles. L is a ligand and is selectedfrom PR′ wherein R′ is selected from alkyl, aryl, alkylaryl, and NR″groups, and R″ is selected from alkyl, aryl, and alkylaryl groups. n canrange from 0-8, and preferably ranges from 0 to 4.

The butyn-2-ol is disclosed in, e.g., U.S. Pat. No. 6,063,847, andMethods A and B may be performed on either the racemic or enantiopurebutynol. The butynol may be combined with a mineral acid, for examplesulfuric acid, in an organic solvent such as THF and a compound such ashexyldimethylsilazane to provide a protecting group on the alcohol. Theprotected compound may then be combined with a suitable base. Apreferred nucleophilic base is hexyllithium. The resulting metallatedcompound may then be amidated by combining it with a solutioncontaining, e.g., diphenylcarbamylimidazole, and deprotected, to yieldthe diphenylamide (Compound 3 wherein R₅ and R₆ are both phenyl).

The amide may then be converted to Compound 2 via either of two routes:through vinyl alcohol 4, or through amide 7. For example, amide 3 may becombined with nitro acid 6. In one embodiment, amide 3 reacts with amixed anhydride of the nitro acid 6 (prepared from 6 and pivaloylchloride in the presence of a tert-amine base), in the presence of DMAPto form Compound 7. The amide is subsequently subjected to hydrogenationconditions to yield Compound 2. Preferred hydrogenation conditionsinclude pressurized hydrogen in the presence of a hydrogenationcatalyst. The hydrogen pressure may range from 20 to 500 psi, and apressure of 100 psi is preferred. The hydrogenation catalyst may be anoble metal catalyst, for example Lindlar catalyst. The hydrogenation issuitably conducted in the presence of a solvent, preferably an aromaticsolvent such as toluene.

The yields in the above-described syntheses of Compound 3 can beimproved by suppressing side- or over-reactions that can occur as theproduct (Compound 3) comes in contact with its precursors. These side-or over-reactions can be suppressed by decreasing the residence time ofthe final process step (the step resulting in Compound 3). Thisreduction of residence time can be achieved by using a suitable flowoperation rather than a batch operation at this step. The reactants areintroduced in individual reactant streams which are combined andimmediately mixed in a flow-through step. This can be achieved bycombining the individual flow streams at a point near the inlet of apump, and pumping the combined reactant stream through a static mixer,followed by immediate quench.

Alternatively, amide 3 may be reduced to the corresponding vinyl alcohol4, and the alcohol is then reacted with nitro acid 6 to yield Compound2.

Compound 2 is subsequently cyclized to yield Compound 1. The cyclizationof 2 is conducted in a suitable solvent (e.g., hydrocarbons such asxylene, N-methylpyrrolidinone, Dimethylsulfoxide, diphenyl ether,Dimethylacetamide and the like as well mixtures of 2 or more thereof),at elevated temperature (e.g., between about 70 and about 190° C.,preferably between about 80 and about 170° C., more preferably betweenabout 100 and about 160° C., still more preferably between about 120 andabout 150° C.), to produce a mixture of exo- and endo-isomers. Thismixture is treated with a suitable base to complete the epimerization atthe trans[5,6]-ring-junction (29) to the cis-isomer (30). The resultingmixture comprises the α- and β-isomers of each Compound 29 and 30, for atotal of four isomers. The α-isomer of Compound 30 is a desirableintermediate in the synthesis of himbacine analogs, and is hereindesignated Compound 1.

The resulting mixture is dynamically resolved by treatment with asuitable base and preferential crystallization of the desired α-isomerusing a suitable solvent. The equilibrium concentrations of the α- andβ-isomers in solution are a function of the pH of the solution, whichcan be modified by addition a suitable base. Thus, the β-isomers can beconverted to the desired α-isomers by addition of a suitable base.Simultaneously, in the presence of a suitable solvent, the α-isomerprecipitates from the solution as a solid. In the dynamic resolutionprocess, this precipitation tends to deplete the α-isomer from thesolution, driving the equilibrium of the β to α conversion process fromthe β-isomer towards the α-isomer in the solution.

Suitable bases for the steps include, for example, triethylamine,1,5-diazabicyclo[4,3,0]non-5-ene 1,4-diazabicyclo[2,2,2]octane, and1,8-diazabicyclo[5,4,0]undec-7-ene, or mixtures of 2 or more thereof.Suitable solvent for crystallization includes hydrocarbon, alcohols,ethers, ketones, esters, xylene, N-methylpyrrolidinone. In someembodiments, the solvent is selected from ethanol, isopropyl alcohol,aryl alcohol alcohols, ethers, ketones, esters, xylene,N-methylpyrrolidinone, and the mixtures of 2 or more thereof.Advantageously, the exo-endo ratio for Compound 1 may exceed 90:10, andmay also exceed 95:5. The α:β ratio at the nitro position may exceed95:5, and for example may be 98.1:1.5.

The carbon-carbon double bond and the nitro group of Compound 1 may thenbe reduced under suitable reduction conditions to yield amine 12.Suitable reduction conditions may include contact with a hydrogenationcatalyst, such as one selected from standard noble metal catalysts(e.g., palladium on carbon, platinum on carbon, and rhodium on carbon,or a mixture thereof). The source of hydrogen can be hydrogen gas,formic acid, formates, and combinations thereof. Multiple catalysts mayalso be used. Amine 12 may then be converted to carbamate 13 by reactionwith an alkyl haloformate (e.g., ethylchloroformate, ethylbromoformate,or ethyliodoformate). Carbamate 13 may then be converted to thecarbamate acid 14 by reaction with a base such as, for example, a metaloxide or hydroxide, carbonate and bicarbonate, where the metal isselected from the group consisting of lithium, sodium, potassium, andmagnesium, followed by reaction with a mineral acid. Sodium hydroxide isa preferred base. The acid 14 is subsequently converted to thecorresponding aldehyde 15, which is reacted with phosphorus ester 16 toyield Compound 1.

Compound 6 may be prepared from acrolein and nitromethane following thescheme below. Nitromethane is treated with an inorganic base such asmetal hydroxide (e.g., LiOH, KOH, NaOH, Ca(OH)₂), metal carbonate (e.g.,Li₂CO₃, Na₂CO₃, K₂CO₃, Cs₂CO₃) and acrolein in a C₁ to C₈ alcohol (e.g.,methanol, ethanol, propanol, isopropanol, butanol, sec-butanol,t-butanol, pentanols, and octanols) or a mixture of alcohols to givecrude Compound 8. To purify Compound 8, crude Compound 8 is isolated asits metal bisulfite salt 9 by treating with a metal bisulfite reagentselected from, NaHSO₃, KHSO₃, Na₂S₂O₅, and K₂S₂O₅. The bisulfitecompound 9 is converted to the purified 8 by treating with a lower alkylcarbonyl compound (e.g., acetaldehyde, acetone, glyoxylic acid, or asalt of glyoxylate), and a carbonate base (e.g., LIHCO₃, NaHCO₃, KHCO₃,Na₂CO₃, K₂CO₃) in a biphasic system containing water and awater-immiscible solvent.

The compound 8 is cyclized by treating with a secondary amine (e.g.,piperidine, pyrrolidine, piperazine, dialkylamines, anddiarylalkylamines) and a carboxylic acid (e.g., aliphatic and aromaticcarboxylic acids) in an organic solvent (e.g., CH₂Cl₂, chlorobenzene,t-butylmethylether, or toluene) to produce Compound 10.

There are two methods to convert Compound 10 to Compound 6, designatedherein as Method C and Method D. In Method C, Compound 10 is firstconverted to Compound 6A by reacting 10 with a Wittig reagent. The R₈ inthe Wittig reagent given in the scheme below is selected from C₁ to C₁₀alkyl or arylalkyl groups. The Compound 6A is then converted to Compound6 via an inorganic base- or acid-catalyzed hydrolysis. The applicableinorganic bases include, but are not limited to, alkaline hydroxide,carbonate, and phosphate bases. The applicable acids include, but arenot limited to mineral and organic acids.

In method D, Compound 10 is converted directly to Compound 6 by reacting10 with malonic acid in a suitable solvent or solvent mixture (e.g.,hydrocarbon solvent including halogenated solvent, aromatic solvent andnitrogen-containing solvents). In some embodiments, the solvent iseither pyridine or toluene, or a mixture thereof. Optionally, a catalyst(e.g., piperidine, pyrrolidine, piperazine, pyridine, and triethylamine)can be introduced to accelerate the reaction.

Compound 16 can be prepared following the scheme below starting from5-bromo-2-methylpyridine N-oxide. The 5-bromo-2-methylpyridine N-oxideis first converted to Compound 35 by treating with an anhydride (e.g.,aromatic acid anhydride, acetic anhydride, or trihalogenated aceticanhydride) in an applicable solvent (e.g., esters, C₁ to C₁₀ hydrocarbonsolvent, or aromatic solvents, or a mixture thereof). Compound 35 isconverted to Compound 36 by treatment with an alcohol (e.g., methanol,ethanol, propanol, isopropanol, butanols, and pentanols) at an elevatedtemperature of about 20 to about 80° C., preferably, about 30 to about70° C., more preferably about 45 to about 55° C.

The synthesis of Compound 37 (with X being Cl) is disclosed in van denHeuvel, Marco et al, J. Org. Chem., 69, 250-262 (2004). According to thepresent invention, Compound 36 is converted to Compound 37 according tothe scheme below, by reacting with a leaving group reagent including ahalogenating reagent (e.g., SOCl₂, SOBr₂, PCl₃, PBr₃, PCl₅, or PBr₅) oranother proper leaving group reagent. In the scheme below, X is aleaving group selected from Halogens, esters, sulfonates, andphosphates.

Compound 37 is converted to Compound 38 by treating with a phosphitereagent. The phosphite reagent can be prepared from a dialkylphosphiteor a diarylphosphite (e.g., (R₉O)₂P(O)H, wherein R₉ is selected fromC₁-C₁₀ alkyl, aryl, heteroaryl, and arylalkyl groups) and a strong base(e.g., metal hydrides, R₁₀Li, and ((R₁₀)₃Si)₂NLi, wherein R₁₀ isselected from C₁ to C₁₀ alkyl and aryl groups).

Compound 38 is converted to Compound 16 by reacting with afluoroaromatic borate reagent, 3-FC₆H₄B(OR₁₁)₂, wherein R₁₁ is selectedfrom a group consisting of C₁ to C₁₀ alkyls, aryls, heteroaryls andhydrogen. The reaction is catalyzed using a palladium catalyst, PdL_(n),wherein L is a ligand selected from PR′₃ wherein R′ is selected fromalkyl, aryl, alkylaryl, and NR″₃ wherein R″ is selected from alkyl,aryl, and alkylaryl. Alternately, palladium on carbon (“Pd/C”) may beused as the catalyst. The preferred ligands are PPh₃, P(o-Tol)₃, andbipyridine.

The following illustrates a general scheme for the synthesis of Compound11 via the nitro-oxazole route:

(R)-butynol may advantageously be protected with, for example, THP. TheTHP-protected alcohol may then be permitted to react with a substitutedbenzothiazole, for example 2-chlorobenzothiazole, to yield Compound 23(where X is S). The reaction may be conducted in a solvent, for examplean organic solvent such as DMF, and in the presence of a base, forexample triethylamine. Compound 23 may then be converted to Compound 22by either of two routes: through vinyl alcohol 25, or through Compound24. The latter route may be conducted by reacting Compound 23 with nitroacid 6 in the presence of an aromatic solvent such as, for example,toluene, to yield Compound 24. Compound 24 is subsequently reduced underhydrogenation conditions, for example in the presence of hydrogen and aLindlar catalyst, to yield Compound 22. Compound 22 is then cyclized viaa Diels-Alder reaction, followed by treatment with a base to yieldCompound 21. The cyclization of 22 is conducted in a suitable solvent(e.g., hydrocarbons such as xylene, N methylpyrrolidinone,Dimethylsulfoxide, diphenyl ether, Dimethylacetamide and the like aswell mixtures of 2 or more thereof), at elevated temperature (e.g., fromabout 70 to about 190° C., preferably from about 80 to about 170° C.,more preferably from about 100 to about 160° C., still more preferablyfrom about 120 to about 150° C.), to produce a mixture of exo- andendo-isomers. This mixture is treated with a suitable base to completethe epimerization to produce the cis-isomer (21). Suitable basesinclude, for example, triethylamine, 1,5-diazabicyclo[4,3,0]non-5-ene,1,4-diazabicyclo[2,2,2]octane, and 1,8-diazabicyclo[5,4,0]undec-7-ene.

The following illustrates a general scheme for the synthesis of Compound11 via the nitro-ester route:

(R)-butynol is converted to a benzyl ester 28 (where R₇ is benzyl).Compound 28 reacts with the mixed anhydride of the nitro acid 6(prepared from 6 and pivaloyl chloride in the presence of a tert-aminebase), in the presence of DMAP, to form Compound 19. Compound 19 isreduced under hydrogenation conditions, e.g., in the presence ofhydrogen and a Lindlar catalyst, to yield ester 18. Ester 18 issubsequently cyclized to yield Compound 17 as follows. The cyclizationof 18 is conducted in a suitable solvent (e.g., hydrocarbons such asxylene, N-methylpyrrolidinone, Dimethylsulfoxide, diphenyl ether,Dimethylacetamide and the like as well mixtures of 2 or more thereof),at elevated temperature (e.g., from about 70 to about 230° C.,preferably, from about 80 to about 170° C., more preferably, from about130 to about 160° C., still more preferably, from about 140 to about150° C.), to produce a mixture of exo- and endo-isomers. This mixture istreated with a suitable base to complete the epimerization to thecis-isomer 17 as described previously. The carbon-carbon double bond andthe nitro group of Compound 17 may then be reduced under suitablereduction conditions to yield amine 20. Suitable reduction conditionsmay include contact with a hydrogenation catalyst, such as one selectedfrom standard noble metal catalysts. Multiple catalysts may also beused. A preferred reduction catalyst is palladium on carbon. The sourceof hydrogen can be hydrogen gas, formic acid, formates, and combinationsthereof.

The experimental conditions disclosed herein are preferred conditions,and one of ordinary skill in the art can modify them as necessary toachieve the same products.

EXAMPLES Example 1 Preparation of 3-(5-Nitro-cyclohex-1-enyl)-acrylicacid (Compound 6) and its Salt A. Preparation of Compound 9 fromAcrolein

To a solution of potassium hydroxide (3.1 g, 0.05 mol) in methanol (450ml) were added nitromethane (39 ml, 0.69 mol) and isopropanol (450 ml)under nitrogen atmosphere. The resulting mixture was cooled to atemperature between −20° C. and −25° C. Acrolein (120 ml, 1.74 mol) wasthen added slowly in about 3 to 3.5 hours while maintaining thetemperature between −20° C. and −25° C. After stirring at the sametemperature for 1 hour, the reaction was quenched with acetic acid (4ml). The reaction mixture was warmed up to room temperature and asolution of sodium metasulfite (135 g, 0.67 mol) in water (700 ml) wasslowly added at about 25° C. After stirring the resulting suspension for1 hour, the mixture was cooled to 10° C. and stirred for another hour.White solid was obtained after filtration and drying under vacuum. Theproduct was carried to the next step without further purification.Yield: 219 g, 83%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.41-1.64 (m, 2H),1.76-1.99 (m, 6H), 3.79-3.85 (m, 2H), 4.63 (m, 1H), 5.44 (t, J=6.2 Hz,2H).

B. Preparation of 4-Nitro-heptanedial

To a suspension of sodium 1,7-dihydroxy-4-nitro-heptane-1,7-disulfonate,9, (219 g, 0.57 mol) in methylene chloride (1.6 L) was added a solutionof glyoxylic acid (160 g, 1.7 mol) and sodium bicarbonate (150 g, 1.78mol) in water (2 L). The resulting mixture was stirred at roomtemperature for 30 to 60 minutes until all solids were dissolved. Theorganic layer was split and the aqueous layer was extracted withmethylene chloride twice (2×400 ml). Combined extracts were thenconcentrated to give a colorless oil. The product was carried to nextstep without further purification. Yield: 85 g, 86%. ¹H NMR (400 MHz,CDCl₃) δ 2.09-2.24 (m, 4H), 2.58 (m, 4H), 4.61 (m, 1H), 9.77 (s, 2H).¹³C NMR δ 26.2, 39.9, 86.9, 200.0.

C. Preparation of 5-Nitro-cyclohex-1-enecarbaldehyde

To a solution of 4-Nitro-heptanedial (35.2 g, 0.2 mol) in methylenechloride (0.7 L) were added pyrrolidine (2 ml, 0.024 mol) and benzoicacid (1.46 g, 0.012 mol), and the resulting mixture was refluxed for 10to 15 hours. The reaction mixture was cooled to room temperature, washedwith 1N HCl (170 ml), saturated with NaHCO₃ (170 ml) and water (170 ml)and concentrated to give brownish oil with a purity of about 80%. Theproduct was carried to the next step without further purification.Yield: 32.2 g, 75%. ¹H NMR (400 MHz, CDCl₃) d 2.29-2.34 (m, 2H),2.46-2.64 (m, 2H), 2.85-2.88 (m, 2H), 4.74 (m, 1H), 6.86 (m, 1H), 9.50(s, 1H).

D. Preparation of 3-(5-Nitro-cyclohex-1-enyl)-acrylic acid

To a solution of 5-nitro-cyclohex-1-enecarbaldehyde (18 g, 0.116 mol) inpyridine (36 ml) was added masonic acid (41 g, 0.394 mol). The resultingsuspension was heated to 60° C. for about 7 hours. After cooling to atemperature between 15° C. and 20° C., 6N HCl (72 ml) was slowly addedinto the reaction mixture to adjust the pH to between 1.5 and 2 whilemaintaining the temperature between 20° C. and 25° C. The mixture wasthen extracted with methylene chloride three times (1×180 ml, 2×90 ml).The combined extracts were washed with 1N HCl (48 ml), water (48 ml) andconcentrated to a volume of 36 ml. The concentrate suspension was cooledto 0° C. and 5° C. for 1 hour. Light yellow solid was obtained afterfiltration and drying under vacuum. Yield: 10 g, 60%. Mp 158-160° C.¹HNMR (400 MHz, DMSO-d₆): δ 2.10-2.33 (m, 4H), 2.73 (m, 2H), 4.96 (m,1H), 5.83 (d, J=20 Hz, 1H), 6.28 (s, 1H), 7.27 (d, J=20 Hz, 1H), 12.3(s, 1H).

Example 2 Alternative Method for Preparing3-(5-Nitro-cyclohex-1-enyl)-acrylic acid (Compound 5) via Wittig Reagent

To a solution of 10 (67 g, 432 mmol) in 1 L of methanol at 0° C. wasadded 144.4 g (432 mmol) of the Wittig reagent. The resulting mixturewas agitated at 0° C. for 3 hrs. The solvent was removed under reducedpressure. The residue was extracted with MeOBu-t twice. The extract wasfiltered to remove any solid, washed with brine, and concentrated. Theresidue was chromatographed on a silica gel column, eluting withhexane/ethyl acetate (10/1) to give 9.2 g cis and 55.1 g (60.4%) transproduct. ¹H NMR (CDCl₃) d 7.31 (d, J=11.3 Hz, 1H), 6.18 (m, 1H), 5.84(d, J=15.9 Hz, 1H), 4.74-4.68 (m, 1H), 3.76 (s, 3H), 2.81-2.74 (m, 2H),2.50-2.04 (m, 4H).

Next, to a flask were added 2.1 g of the methyl ester, 9.6 ml of MeOHand 2.4 ml of water. To the mixture at about 5° C. was added dropwise0.96 ml of 50% NaOH. The mixture was allowed to warm to room temperatureand stirred at this temperature for about 24 hrs. The reaction mixturewas neutralized with HOAc to pH between 4 and 5 and the methanol wasremoved under reduced pressure. The residue was extracted with 3×50 mlEtOAc. The EtOAc layer was concentrated to give 1.5 g of nitroacid 6(76.5%).

Example 3 Preparation of Compound 3a

The following procedures can be operated on either the racemic or theenantiopure starting butyn-2-ol. To a stirred solution of sulfuric acid(conc., 40 μL) in THF (240 mL) were sequentially added (R)-3 butyn-2-ol(40 g, 0.57 mol) and then hexylmethyldisilazane (49.6 g, 0.31 mol) atroom temperature. The solution was refluxed for 3-4 hours and thenslowly cooled to −40° C. The resulting mixture was slowly charged inhexyllithium (2.5M in hexane, 249 mL, 0.62 mol) while maintaining thetemperature at −40° C. This solution and a solution ofdiphenylcarbamylimidazole (180 g, 0.68 mol) in a mixed solvent of THF(1088 mL) and toluene (435 mL) were mixed using pumps through a chilledstatic mixer and directly quenched into 5N sulfuric acid (560 mL, −5°C.). The quenched solution was warmed to 25° C. and stirred for 1 hour.The organic layer was separated, washed with 5N sulfuric acid (80 mL)and then twice with 10% brine (200 mL each time). The pH of the finalbrine wash was adjusted to 5-7 with a 5% NaHCO₃ solution. The organiclayer was then distilled and replaced with toluene (440 mL). The toluenesolution was added to heptane (400 mL) at 85° C., cooled slowly to 20°C. and filtered. The filtered cake was washed with a mixed solution oftoluene (80 mL) and heptane (80 mL). The cake was then dried in vacuumoven at 50° C. to afford the title compound in 84% molar yield (120.6 g,purity 99%). Mp 105° C. ¹H NMR (400 MHz, DMSO-d₆) δ 1.04 (d, J=6.4 Hz,3H), δ 4.27 (dq, J=5.6 Hz, 6.4 Hz, 1H), δ 5.49 (d, J=5.6 Hz, 1H), δ7.2-7.5 (m, 10H); ¹³C NMR (DMSO-d6) δ 23.7, 56.3, 76.9, 96.4, 126.8,127.0, 128.5, 129.2, 129.4, 129.6, 141.5, 142.2, 152.9.

Example 4 Preparation of Compound 7a

To a flask were charged sequentially Compound 6 (90 g, 0.46 mole) andtoluene (500 mL). The suspension was cooled to about 0° C., andN-methylmorpholine (91 mL, 0.83 mole) and trimethylacetyl chloride (56mL, 0.46 mole) were slowly added while keeping the reaction temperaturebelow 5° C. The reaction mixture was agitated for 1 hour at 0° C. andassayed for completion of formation of mixed anhydride (<10% of UBremains). A solution of 3a (100 g, 0.38 mole) in toluene (400 mL) andTHF (220 mL) was added while keeping the reaction temperature below 5°C. This was followed by addition of a solution of4-dimethylaminopyridine (5.5 g, 0.046 mole) in THF (45 mL). The mixturewas agitated at about 0° C. for 8-12 hours until reaction completion(<0.2% EB remains). Reaction was quenched by adding a solution of 2.0 NH₂SO₄ (400 mL), warmed up to 25° C. and filtered through a pad ofcelite. The layers were separated and the organic layer was washed with5% K₂CO₃ solution (3×300 mL) to remove excess 6 (<1% of 6 remains). Themixture was washed with 5% NaCl. solution (300 mL), filtered through apad of celite, and concentrated to about 500 mL final volume. Solutionyield 90-95%. ¹H NMR (CDCl₃, 400 MHz) δ 7.05-7.35 (m, 11H), 6.13 (br,1H), 5.62 (dd, J=16, 4 Hz, 1H), 5.31 (q, J=7 Hz, 1H), 4.67 (m, 1H),2.62-2.78 (m, 2H), 2.58 (br, 2H), 2.05 (m, 2H), 1.22 (d, J=7 Hz, 3H).

Example 5 Preparation of Compound 2a

To a solution of 7a in toluene (200 mL, 50.0 g active, 112.5 mmol) werecharged Lindlar catalyst (2.5 g of 5% Pd/CaCO₃ with 5% Pb poisoned, 1.2mmol) and quinoline (1.5 mL, 11.6 mmol). The mixture was hydrogenatedusing 100 psi hydrogen at 25-30° C. until reaction completion as judgedby HPLC. After removal of catalyst by filtration, toluene was replacedwith ethyl alcohol by regulated vacuum distillation of about 40° C. Theproduct was dynamically crystallized from ethyl alcohol (180 mL) at 40°C. in the presence of triethyl amine (8.5 mL). The reaction mixture wasslowly cooled to 5° C. over a period of 4 hours. After stirring at 5° C.for 3 hours, the product was filtered and washed with cold ethylalcohol. The product was dried at 60° C. in a vacuum oven with nitrogenpurge overnight to give 2a as a yellow crystalline solid. Yield: 73.7%.Mp 113-115° C. ¹H NMR (400 MHz, CDCl₃) δ 1.48 (d, J=6.4 Hz, 3H),2.21-2.46 (m, 4H), 2.80 (m, 2H), 4.71 (m, 1H), 5.81-5.91 (m, 3H), 6.19(m, 1H), 6.29 (q, J=6.4 Hz, 1H), 7.28-7.37 (m, 11H).

Example 6 Preparation of Compound 1a

Into a 2 L 3-neck round bottom flask was placed 2a (25 g, 0.056 mol) andethyl acetate (210 mL). The contents were stirred until Compound 2acompletely dissolved. The solution was washed with 0.25 M H₂SO₄ (75 mL)and with water (3×75 mL). The organic phase was concentrated underreduced pressure to about 200 mL, and 1-methyl-2-pyrrolidinone (50 mL)was added. The solution was heated under distillation mode until atemperature of 145° C. was attained. The solution was held at thistemperature for 3.5 h. The solution was cooled to room temperature, andDBU (0.57 mL, 6.8 mol %) was added. The solution was stirred for 1 h andwas quenched with 0.1 M H₂SO₄ (125 mL) and the product was extractedinto ethyl acetate (125 mL). The organic phase was washed with water(125 mL) and was treated with DARCO-G60 (2.5 g) at 65° C. for 1 h. Thesuspension was filtered through a pad of Celite while the solutionremained hot. The solution was concentrated by atmospheric distillationto 38 mL. The remaining ethyl acetate was replaced with isopropylalcohol by azeotropic distillation. The volume of the solution wasadjusted to 225 mL. The solution was diluted with ethyl alcohol(denatured with 0.5% toluene, 100 mL). The solution was slowly cooled toabout 65° C., and DBU (0.29 mL, 3.4 mol %) was added. The suspension wasslowly cooled to 15° C. and held at this temperature for 5 h. Theproduct was filtered and washed with a 2:1 mixture of isopropyl alcoholand ethyl alcohol (50 mL). 19.3 g was obtained upon drying for 24 h at50° C. (90.2 wt % purity, 17.4 g active, 72.5% yield). Mp 151.8° C. ¹HNMR (400 MHz, CDCl₃): δ 0.99 (m, 1H), 1.56 (d, J=6.0 Hz, 3H), 2.03 (m,1H), 2.25-2.31 (m, 1H), 2.42-2.53 (m, 2H), 2.62-2.76 (m, 3H), 2.86-2.91(m, 1H), 2.96-3.00 (m, 1H), 4.28-4.36 (m, 1H), 4.67-474 (m, 1H), 5.42(br s, 1H), 7.22-7.53 (m, 10H).

Example 7 Preparation of Compound 13a

To a three-neck flask equipped with an agitator, thermometer andnitrogen inlet were sequentially added 1a (100 g), THF (600 ml), 10%palladium on carbon (50% wet, 35 g) and water (400 ml). The mixture wasagitated for about 10 minutes at room temperature and then heated toabout 50° C. Formic acid (70 ml) was added slowly while the temperaturewas maintained between 45 and 55° C. The reaction mixture was agitatedfor 4 hours at 45-55° C. After the reaction was judged complete by HPLC,the reaction mixture was cooled to 20° C. and the pH was adjusted to 1-2with 25% H₂SO₄ (60 mL). THF (200 mL) was added to the reaction mixture,which was then filtered through a pad of Celite to remove the catalyst.A mixed solution of THF (300 mL), water (300 ml) and 25% H₂SO₄ (5 mL)was used to rinse the flask and catalyst, and filtered through theCelite. The combined solution containing compound 12a was charged backinto a clean flask and the mixture was cooled to below 10° C. The pH wasadjusted to about 9 with 25% NaOH (30 mL) at below 10° C. and NaCl (150g) was then added. The mixture was warmed to 20° C. and two phases wereseparated. The aqueous phase was extracted with THF (400 mL) and thecombined organic phases were washed with a brine solution (40 g of NaClin 200 mL of water). The organic layer was cooled to 5° C. and triethylamine (56 mL) was added. Then ethyl chloroformate (23.6 mLml) was addedslowly. The mixture was warmed to 20° C. and stirred for 30 minutes.After the reaction was judged complete, 200 ml of MTBE and 100 mL ofwater were added to the reaction mixture, followed by the slow additionof 100 mL of 25% H₂SO₄. The two phases were separated and the organiclayer was washed with 200 ml of 12% H₂SO₄. The organic layer was thenconcentrated and azeotropically distilled with 2B ethanol and 250 mlwater was added at 70-80° C. The compound 13a was precipitated out fromethanol-water with seeding at 55-65° C. After agitating for 1 hour at55-65° C., 150 ml water was added at this temperature and held for 1hour. After cooling to 15-25° C., the mixture was agitated for anadditional 3 hours at 15-25° C. and then the product was filtered andwashed with ethanol-water. The product was dried at 50-60° C. to providean off-white solid (86 g, Yield: 85%). Mp 188.2° C. ¹HNMR (CDCl₃) δ7.25-7.55 (m, 10H), 4.89 (m, 1H), 4.51 (bs, 1H), 4.09 (d, J=6.98 Hz,2H), 3.49 (brs, 1H), 2.41 (m, 2H), 2.25 (m, 1H), 2.06 (d, J=10.8 Hz,2H), 1.96 (d, J=10.9 Hz, 1H), 1.83 (ddd, J=13.5, 6.09, 2.51 Hz, 1H),1.63 (m, 1H), 1.52 (d, J=5.8 Hz, 3H), 1.23 (m, 5H), 1.17 (q, J=11.5 Hz,2H), 0.92 (q, J=11.5 Hz, 1H). MS (ESI) for M+H calcd. 491 Found: 491.

Example 8 Preparation of Compound 14a

To a 250-mL 3-neck flask equipped with an agitator, thermometer, and areflux condenser, were added 10 g of 13a (20.4 mmol) and THF (50 mL). Tothis solution was added an aqueous solution of 5% (w/w) sodium hydroxide(50 mL). The reaction mixture was then heated to and agitated at 40° C.for about 4 hours. When the hydrolysis reaction was judged complete,toluene (50 mL) was added and the mixture was agitated at a rather fastrate for about 10 minutes. The organic phase containing the by-productwas separated from the aqueous phase containing product. The organicphase was back-extracted with 5% aqueous NaOH solution (50 mL). Thecombined aqueous solutions were extracted twice with toluene (2×50 mL)and the organic extracts were discarded. To the aqueous solution wereadded a solvent mixture of toluene (25 mL) and THF (50 mL). Theresulting mixture was cooled to between 0 to 5° C. A 2 N hydrochloricacid aqueous solution (about 59 mL) was added to adjust the pH of themixture from ˜13 to 2.5 at 0 to 5° C. The aqueous phase was thenseparated from the organic phase and extracted with a solvent mixture oftoluene (25 mL) and THF (50 mL). The organic phase and organic wash werecombined and diluted with THF (50 mL). The mixture was then concentratedatmospherically to a final moisture content of ≦0.05% by repeateddistillations, if necessary. The crude product was used in the next stepwithout further isolation and purification (containing 6.80 g, 99%yield). ¹H-NMR (CD₃CN) δ 9.72 (bs, 1H), 7.17-7.41 (Ph in toluene), 5.45(bs, 1H), 4.68 (dt, J=5.90, 16.0, 1H), 4.03 (q, J=7.10, 2H), 3.45-3.50(m, 1H), 2.50-2.65 (m, 2H), 2.45 (dd, J=5.64, 11.5, 1H), 2.36 (methyl intoluene), 1.83 (m, 4 protons), 1.34-1.50 (qt, J=2.91, 11.0, 1H), 1.32(d, J=5.91, 3H), 1.15-1.25 (m, 6H), 0.95-1.05 (m, 2H).

Example 9 Preparation of Compound 36

To a solution of 5-bromo-2-methylpyridine N-oxide (10.0 g, 5.32 mmol) inEtOAc (50.0 ml) at 0° C. was added dropwise trifluoroacetic anhydride(9.8 ml, 6.92 mmol.) while keeping the temperature below 50° C. Afterthe completion of the addition, the mixture was heated to between 75 and80° C. and stirred for at least 1 h. HPLC assay of the mixture indicatedreaction completion when 5-bromo-2-methylpyridine N-oxide is <5%.

Upon completion, the mixture was cooled below 50° C. and MeOH (10.0 ml)was added. The mixture was heated for at least 1 h at 50° C. Thesolution was concentrated under vacuum and MeOH was removed bydisplacement with EtOAc (40.0 ml) and concentrated to a volume of 30 ml.To the concentrate was added toluene (20.0 ml) and the solution cooledto −10° C. over 2 h. The crystalline solid was filtered and washed withcold toluene and dried overnight under vacuum at 35° C. to provide 10.1g (63%) of 36. Mp 89-92° C. ¹H NMR (DMSO-d₆) δ 4.56 (s, 2H), 7.49 (d,1H), 8.1 (dd, J=2.3, 2.3 Hz, 1H), 8.64 (d, J=2.1 Hz, 1H).

Example 10 Preparation of Compound 16

A. Preparation of 37

A slurry of 36 (10.0 g, 33.1 mmol) in TBME (100 ml) was treated with 20%potassium carbonate (20 ml) solution and stirred at room temperature for1 h. The layers were separated and the organic layer was washed withwater. The TBME and water were removed by atmospheric distillation andazeotropic distillation with acetonitrile (100 ml) and furtherconcentrated under vacuum to a volume of 40 ml. A Karl Fischer wasperformed to confirm the removal of water (KF≦0.2). To the acetonitrileconcentrate was added dropwise thionyl chloride (3.2 ml, 43.7 mmol)while keeping the temperature below 45° C. The reaction mixture was thenheated at 45° C. for 2 h at which time an HPLC assay indicated completereaction. The reaction mixture was cooled to 25° C. and quenched withwater (20 ml) while keeping the temperature below 40° C. The reactionmixture was slowly poured into a mixture of 20% sodium carbonate (40 ml)and toluene (100 ml), stirred for 10 min and the layers werepartitioned. The toluene extract was concentrated under reduced pressureto a volume of about 20 ml. A KF was performed to confirm the removal ofwater (KF≦0.2).

B. Preparation of 38

To a dry reaction vessel was charged a solution of lithiumbis(trimethylsilyl) amide 1.3M in THF (51 ml, 66.2 mmol) and diethylphosphite (13 ml, 101.6 mmol) while keeping the temperature under 25° C.The solution was stirred at 25° C. for at least 1 h. The toluenesolution containing 37 from above was added over 1 h and the resultingmixture was stirred at 25° C. for at least 2 h at which time an HPLCassay indicated complete reaction. Upon completion, the solution wasquenched into 5% sodium chloride (50 ml). The aqueous layer wasextracted with toluene (50 ml). The combined organic layer wasconcentrated under reduced pressure to a volume of about 20 ml. Toluene(80 ml) was then added and the solution was washed with a 20% solutionof potassium carbonate to remove diethyl phosphate, confirmed by ¹H NMR(<20 mol %). The toluene solution was then washed with water andconcentrated under reduced pressure to a volume of about 40 ml ofCompound 38 solution.

C. Preparation of 16

To a reaction vessel was charged sodium carbonate (8 g; 75.5 mmol), 30ml of water and stirred until dissolved. To this solution were added3-fluorophenylboronic acid (6 g; 42.9 mmol) and 5% Pd/C 50% wet (0.5 g).The toluene solution of Compound 38 from above was then added and themixture was heated to 75° C. for at least 5 h at which time an HPLCassay indicated complete reaction. Upon completion, the reaction mixturewas cooled to 25° C. and filtered to remove the Pd/C catalyst. Thelayers were separated and the organic layer was washed and concentratedunder reduced pressure to about 20 ml. Heptane (20 ml) was slowly added,seed crystals were added, and the mixture was cooled to −10° C. over 2h. The crystalline solid was filtered, washed with heptane and driedovernight under vacuum at 30° C. to provide 8 g (75%). Mp 61-63° C. δ1.3 (t, J=7.08 Hz, 3H), 3.42 (s, 1H), 3.49 (s, 1H), 4.1 (q, J=7.08 Hz,2H), 7.04-7.11 (m, 1H), 7.23-7.3 (m, 1H), 7.32-7.3 (m, 1H), 7.32-7.36(m, 1H), 7.39-7.48 (m, 1H), 7.81 (ddd, J=8.08, 2.3, 0.41 Hz, 1H), 8.74(d, J=2.36, 1H).

Example 11 Preparation of Compound 23a

To a flask were added 21 g (124 mmol) of 2-chlorobenzothiazole chloride,30 g of KI, 150 ml of DMF, 2.7 g of CuI, 8.4 g of Pd(PPh₃)₄, 50 ml ofEt₃N, and 118 ml of THP protected (R)-butynol. The mixture was stirredat room temperature for 18 hrs. Most of the solvent was removed underreduced pressure. Water was added and the product was extracted with amixture of t-BuOMe and hexane. The organic layer was washed with brineand concentrated to give an oil. The oil was dissolved in 250 ml of MeOHand treated with TsOH for the deprotection. The mixture was heated at50° C. for a few hrs. The pH was adjusted to between 7 and 8 with NaOH.Most of the solvent was removed. The residue was chromatographed on asilica gel column, eluting with EtOAc/hexane to give 19.7 g of 23a(78%). ¹H NMR (CDCl₃) δ 7.98-7.96 (m, 1H), 7.76-7.74 (M, 1H), 7.45-7.33(m, 1H), 4.82-4.76 (m, 1H), 3.43 (d, J=5.4 Hz, 1H), 1.55 (d, J=6.7 Hz,3H).

Example 12 Preparation of Compound 24a

The same procedure for the preparation of In described above in Example4 was followed starting with 15 g of 23a to give, after columnpurification, 17 g of 24a. ¹H NMR (CDCl₃) δ 7.99-7.97 (m, 1H), 7.79-7.77(m, 1H), 7.48-7.35 (m, 2H), 7.31 (d, J=15.9 Hz, 1H), 6.15 (bs, 1H),5.80-5.74 (m, 2H), 4.72-4.58 (m, 1H), 2.82-2.65 (m, 2H), 2.50-2.05 (m,4H), 1.61 (d, J=6.7 Hz, 3H).

Example 13 Preparation of Compound 22a

The same procedure for the conversion of 7 to 2 (Example 5) was followedstarting from 15 g of 24a to give, after column purification, 17 gproduct. ¹H NMR (CDCl₃) δ 8.18 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz,1H), 7.45-7.37 (m, 1H), 7.32-7.28 (m, 1H), 7.24 (d, 15.8 Hz, 1H), 6.59(dd, J=11.8, 1.3 Hz, 1H), 6.55-6.40 (m, 1H), 6.15-6.08 (m, 1H), 6.00(dd, J=11.8, 8.2 Hz, 1H), 5.76 (d, J=15.8 Hz, 1H), (m, 1H), 2.80-2.65(m, 2H), 2.46-2.05 (m, 4H), 1.50 (m, 3H).

Example 14 Preparation of Compound 21a via Diels-Alder Reaction

The same procedure for the conversion of 2a to 1a (Example 6) wasfollowed starting from 0.34 g of 22a. The ratio of exo:endo wasdetermined by HPLC and NMR and found to be 60:40.

Example 15 Preparation of Compound 19a

To a flask under nitrogen were added 1.48 g of nitro acid 6 and 9 ml oftoluene. To this mixture was added dropwise 2.4 ml of Et₃N to dissolveall solid. To the cooled mixture at between 0 and 5° C. were added 0.9ml of pivaloyl chloride and 30 mg of 4-dimethylaminopyridine (DMAP). Theresulting mixture was stirred at between 0 and 5° C. for 18 hrs. Thereaction mixture was poured into 10 ml of water. The layers wereseparated and the organic layer was washed with NaHCO₃ and water andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column, eluting with Hexane/EtOAc to give 1.56 g of 19a(81%). ¹H NMR (CDCl₃) δ 7.45-7.31 (m, 6H), 6.28-6.18 (m, 1H), 5.81 (d,J=15.9 Hz, 1H), 5.62 (q, J=6.8 Hz, 1H), 5.20 (s, 2H), 4.78-4.68 (m, 1H),3.88-3.70 (m, 2H), 2.52-2.15 (m, 4H), 1.57 (d, J=6.8 Hz, 3H).

Example 15 Preparation of Compound 18a

To a 100 ml Parr flask were added 1.4 g of 19a, 25 ml of toluene, 0.14 gof Lindlar catalyst (Alfa Chem), and 0.1 ml of quinoline. The flask wasevacuated 3 times with nitrogen and vacuum and filled with hydrogen to20 psi. The flask was shaken at room temperature for 3.5 hrs. Themixture was filtered through a pad of celite and washed with toluene.The filtrate was washed with 3×30 ml 1N HCl solution and 30 ml brine.The layers were separated and the organic layer was dried over MgSO₄ andconcentrated to give 1.36 g (97%) of yellow oil. ¹H NMR (CDCl₃) δ7.45-7.10 (m, 7H), 6.41-6.31 (m, 1H), 6.28-6.15 (m, 2H), 5.90-5.78 (m,2H), 5.18 (s, 2H), (m, 1H), 2.88-2.70 (m, 2H), 2.50-2.15 (m, 6H), 1.41(d, J=6.5 Hz, 3H).

Example 16 Preparation of Compound 17a

To a flask were added 0.17 g of 18a and 3 ml of xylene. The mixture washeated to 150° C. for about 6 hrs and cooled to between 30 and 35° C. Tothe cooled mixture was added 1.5 ml of DBU. The resulting solution washeated at between 30 and 35° C. for 1 h to complete the epimerization ofthe initial trans product at the [6,5] junction to the cis product.There were a total of four isomers generated. The exo:endo ratio of theDiels-Alder reaction was about 78:22 and the α:β ratio was about 80:20.The solvent was removed under reduced pressure and the residue waspurified on a silica gel column to give 0.082 g (48%) of the desired exoproduct and 0.025 g (15%) of the endo product. Exo-isomer (α:β mixture):¹NMR (CDCl₃) δ 7.45-7.32 (m, 5H), 5.51 (bs, 1H), 5.22-5.10 (m, 2H), 4.65(bs, 1H, α-isomer), 4.46-4.30 (m, 2H), 3.37-3.30 (m, 1H), 3.14-3.09 (m,1H, β-isomer), 2.94-2.89 (m, 1H), 2.75-1.75 (m, 7H), 1.12 (d, J=6.1 Hz,3H, α-isomer), 1.11 (d, J=5.0 Hz, 3H, β-isomer). Endo-isomer ¹H NMR(CDCl₃) δ 7.40-7.30 (m, 5H), 5.80 (bs, 1H), 5.25 (d, j=11.9 Hz, 1H),4.60 (d, J=11.9 Hz, 1H), 4.58-4.48 (m, 1H), 4.15-4.05 (m, 1H), 3.35-3.25(m, 1H), 3.06 (t, J=5.7 Hz, 1H), 2.95-2.88 (m, 1H), 2.65-2.50 (m, 2H),2.40-2.30 (m, 1H), 2.28-2.20 (m, 1H), (m, 2H), 1.42 (d, J=6.5 Hz, 3H),1.05-0.95 (m, 1H).

Example 17 Preparation of Compound 20

To a Parr flask were added 0.47 g of 17a, 35 ml of EtOAc, and 0.51 g ofPt/C. The flask was evacuated with nitrogen and vacuum 3 times, filledwith hydrogen to 100 psi and was shaken for about 24 hrs as monitored byNMR. The mixture was filtered and washed with MeOH. The filtrate wasconcentrate to give 0.29 g of a gray solid. ¹H NMR (Acetic acid-d₄) δ(α:β=78:22) 4.80-4.68 (m, 1H), 3.78 (bs, 1H, β-isomer), 3.41-3.28 (m,1H, α-isomer), (m, 3H), 2.20-1.00 (m, 10H), 1.33 (d, J=5.8 Hz, 3H).

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications, and variations areintended to fall within the spirit and scope of the present invention.

1. A process for preparing Compound 17:

said process comprising the steps of: (a) cyclizing Compound 18 in afirst solvent at an elevated temperature

wherein R₇ is selected from the group consisting of H, alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, aryl, alkylaryl, arylalkyl, and heteroarylgroups to produce a first mixture comprising α and β of the exo isomersof Compound 17A:

and α and β of the endo isomers of Compound 17B:

said isomers of Compound 17A having a trans-[5,6]-ring-junction; (b)epimerizing said trans-[5,6]-ring-junction of Compound 17A by treatingsaid first mixture with a first base to produce a second mixturecomprising cis-[5,6]-ring-junction-nitro-α isomer andcis-[5,6]-ring-junction-nitro β isomer of each Compound 17C and Compound17B:

and (c) treating said second mixture with a second solvent, causing saidα-isomer of Compound 17C to precipitate to produce Compound
 17. 2. Theprocess of claim 1 further comprising the step of treating said secondmixture with a second base, resulting in a dynamic resolution of saidsecond mixture, in which said β-isomer of Compound 17C is converted toα-isomer of Compound 17C, and α-isomer of Compound 17C is precipitatedto produce Compound
 17. 3. The process of claim 1, wherein said firstsolvent is selected from the group consisting of xylene,N-methylpyrrolidinone, Dimethylsulfoxide, diphenyl ether, andDimethylacetamide, and mixtures of 2 or more thereof.
 4. The process ofclaim 1, wherein said temperature is between about 70 and about 190° C.5. The process of claim 1, wherein said temperature is between about 80and about 170° C.
 6. The process of claim 1, wherein said temperature isbetween about 100 and about 160° C.
 7. The process of claim 1, whereinsaid temperature is between about 120 and about 150° C.
 8. The processof claim 1, wherein said first base is selected from the groupconsisting of triethylamine; 1,5-diazabicyclo[4,3,0]non-5-ene1,4-diazabicyclo[2,2,2]octane; and 1,8-diazabicyclo[5,4,0]undec-7-ene;and mixtures of 2 or more thereof.
 9. The process of claim 1, whereinsaid second solvent is selected from the group consisting of alcohols,ethers, ketones, esters, xylene, and N-methylpyrrolidinone, and mixturesof 2 or more thereof.
 10. The process of claim 1, wherein said secondsolvent is selected from the group consisting of methanol, ethanol,propanols, and butanols, xylene, N-methylpyrrolidinone, and mixtures of2 or more thereof.
 11. The process of claim 2, wherein said second baseis selected from the group consisting of triethylamine;1,5-diazabicyclo[4,3,0]non-5-ene 1,4-diazabicyclo[2,2,2]octane;1,8-diazabicyclo[5,4,0]undec-7-ene; and mixtures of 2 or more thereof.